Mendelian disorders of the epigenetic machinery are a newly delineated group of multiple congenital anomaly and intellectual disability syndromes resulting from mutations in genes encoding components of the epigenetic machinery. The gene products affected in these inherited conditions act in trans and are expected to have widespread epigenetic consequences. The DNA methylation machinery and the histone machinery affect the expression of many genes in trans (Berdasco & Esteller (2013) Hum. Genet. 132:359-83; Wolffe (1994) Trends Biochem. Sci. 19:240-44). Within this group, genetic mutations may occur in writers, erasers, or readers of epigenetic marks. The writers of epigenetic marks, which can be conceptualized as a set of highlighters, place the appropriate modifications on particular regions of the genome based on the cell type, developmental stage, and metabolic state of the cell. These marks “highlight” individual regions for use or disuse depending on whether the mark favors a more open or more closed chromatin state. The erasers of epigenetic marks remove these same marks, favoring the opposite chromatin states. The readers of epigenetic marks recognize and interpret particular marks locally and give cells a mechanism for keeping track of the overall chromatin state.
Mendelian disorders of the histone machinery have been described for writers, erasers, readers, and chromatin remodelers. The histone writer and eraser system is unique because it involves opposing players that must achieve a balance of activity and subsequently of histone marks at particular target genes in any given cell state (FIG. 1). This idea is illustrated by Kabuki syndrome (KS), which can be caused by a defect in either a writer or an eraser. KS is an autosomal dominant or X-linked intellectual disability syndrome with specific dysmorphic features, including a flattened facial appearance with characteristic eyes exhibiting long palpebral fissures, eversion of the lower lids, highly arched eyebrows, and long eyelashes, as well as short stature.
KS is caused by heterozygous loss-of-function mutations in either of two genes with complementary functions, lysine-specific methyltransferase 2D (KMT2D) on human chromosome 12 (also known as mixed lineage leukemia 2 or MLL2; Ng et al. (2010) Nat. Genet. 42:790-3) or lysine-specific demethylase 6A (KDM6A) on human chromosome X (Lederer et al. (2012) Am. J. Hum. Genet. 90:119-24) (FIG. 2). KMT2D is a methyltransferase that adds a trimethylation mark to H3K4 (H3K4me3, an open chromatin mark) while KDM6A is a demethylase that removes trimethylation from histone 3 lysine 27 (H3K27me3, a closed chromatin mark). Both genes facilitate the opening of chromatin and promote gene expression (Ng et al. (2010) Nat. Genet. 42:790-3; Lederer et al. (2012) Am. J. Hum. Genet. 90:119-24; Miyake et al. (2013) Hum. Mutat. 34:108-10).